Our objectives are a better definition of the origin, nature, regulation, effects and significance of Big Renin in human plasma. We have learned to characterize Big Renin by methods which can be applied to plasma, tissue extracts, and other sources, such as amniotic fluid, in which we can demonstrate different forms of Big Renin by gel filtration. We are devising methods to stabilize and detect Big Renin during laboratory processes, and to separate and characterize the several forms. With this information, we can proceed to study questions concerning the origin and regulation of Big Renin in plasma. Big Renin exists in normal kidneys, but the steps by which renal production of Big Renin, its conversion to active renin, and release into plasma are accomplished and regulated cannot be directly observed with current methods. We plan to study Big Renin in plasma of healthy volunteers and selected patients during physiological manipulation and drug administration. Whether Big Renin can play an active physiological role in plasma remains to be determined. In the diabetic patient presenting as hyporeninemic hypoaldosteronism, large amounts of Big Renin in plasma appear to be inactive, but Big Renin secreted by renal tumors can cause hyperaldosteronism. In vitro activation of inactive renin is a technical problem which can lead to serious overestimation of renin activity in clinical studies. We plan to improve our methodology, to characterize the new forms of renin observed in plasma, and to study their significance and effects on human physiology and disease.